Field of the Invention
The present invention relates to the fields of therapeutics and medical compositions. More specifically, the invention relates to methods of treatment for genetic, inflammatory, and other diseases that can be treated with therapeutic levels of carbon monoxide, including sickle cell disease, and to formulations and delivery vehicles that are useful in performing the methods.
Description of Related Art
At the present time, methods and devices for treatment of Sickle Cell Crises (referred to herein as “SCC”) and its prevention are not adequate to manage the disease. The U.S. Centers for Disease Control and Prevention has estimated that 70,000 to 100,000 patients suffer from Sickle Cell Disease (referred to herein as “SCD”) in the U.S., and the life expectancy of these afflicted individuals is only about 40 years. When a patient is admitted to hospital, treatment is symptom-based, mainly by way of morphine-analogue analgesics, fluid replacement, transfusions, and other supportive measures. Currently, the only consistent and reliable method of treatment of SCC is through blood transfusion. However, this treatment method is expensive and inconvenient, and can be dangerous. The use of hydroxyurea to prevent crises has been found to have marginal efficacy and to have side effects, and the response per patient is highly variable. It is also possible to cure SCD through bone marrow transplant, but this procedure is rarely used due to its inherent danger, its high cost, and the co-morbidities of the necessary treatment.
It is known that carbon monoxide (CO) is a poison at high concentrations, interfering with the ability of red blood cells to carry oxygen. It has been reported that hemoglobin (referred herein as “Hb”) saturations of over 67% likely result in CO-induced death unless treatment is provided. Furthermore, Hb saturations of over 30% are reported to result in loss of consciousness, among other serious morbidities, and can result in death if maintained long-term. In addition, Hb saturations between 16% and 20% are reported to result in headache and visual evoked response abnormalities (Stewart RD. The effect of carbon monoxide on humans. Annu Rev Pharmacol 15: 409-423, 1975). As such, extreme caution must be used in situations where CO is present.
However, it is possible that CO can have positive effects in SCD and in other diseases and disorders. For example, it has been reported that CO extends the red cell life span in SCD patients. (Beutler, E., 1975, “The effect of carbon monoxide on red cell life span in sickle cell disease.” Blood 46(2): 253-9.) It has also long been hypothesized that CO might play a role in preventing sickle cell formation by preventing the polymerization of hemoglobin (Sirs, J. A., 1963, “The use of carbon monoxide to prevent sickle cell formation”, Lancet 1, 7288: 971-2). Further, it has been reported that CO might have a preventative effect on the occurrence of clinical symptoms of SCD. (Yallop, D., E. R. Duncan, et al., 2007, “The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment.” Br J Haematol 136(6): 844-8.) The Yallop study documents that there is a decrease in hospital admissions of patients with SCC on days with higher CO content in the breathed air.
Recent research has also found that CO can have more widespread health benefits in multiple diseases and organ systems, including in cardiovascular, kidney, liver, lung, and intestine (Inge Bauer and Benedikt H J Pannen, “Bench-to-bedside review: Carbon monoxide—from mitochondrial poisoning to therapeutic use”, Critical Care 2009, 13:220). Other research points to positive effects in inflammatory and cardiovascular disease (Foresti R, Bani-Hani M G, Motterlini R., “Use of carbon monoxide as a therapeutic agent: promises and challenges”, Intensive Care Med. 2008 Apr;34(4):649-58. Epub 2008 Feb. 20).
In view of the proposed beneficial effects of CO on certain diseases and disorders, a number of efforts using different delivery mechanisms have been made to employ CO as a treatment for disease. These include: delivery of CO gas via pulmonary delivery (Motterlini, R., Otterbein L., “The therapeutic potential of carbon monoxide”, Nat Rev Drug Discov. 2010 Sep;9(9):728-43); the delivery of CO bound to a non-ferrous metal in a small molecule via intravenous infusion, intra-peritoneal injection, or oral ingestion (Motterlini, R., Otterbein L., “The therapeutic potential of carbon monoxide”, Nat Rev Drug Discov. 2010 Sep;9(9):728-43); and the delivery of CO bound to a chemically modified human or bovine hemoglobin tetramer via intravenous infusion (Vandegriff, K. D., M. A. Young, et al. (2008). “CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats.” Br J Pharmacol 154(8): 1649-61; United States patent application publication number 20100311657 Abuchowski, Abraham et al. “HEMOGLOBIN COMPOSITIONS” December 9, 2010; and United States patent application publication number 20090082257 Winslow, Robert M. “MalPEG-Hb conjugate-containing compositions for delivering carbon monoxide (CO) to cells” Mar. 26, 2009). However, these efforts face a number of significant problems and shortcomings.
With regard to delivery of CO gas via inhalation, a number of problems exist that have precluded its clinical use. One of the primary reasons for the lack of clinical use relates to the importance of dosage in CO administration. The efficacious dose of CO is relatively close to its toxic dose. This makes pulmonary delivery difficult given differences in lung function in various diseases, including in SCD. A second complication is that CO is excreted through the lungs. As such, pulmonary delivery of CO requires uptake and excretion through the same organ, significantly complicating pharmacokinetics and determinations of safety. Another challenge with pulmonary delivery is that pulmonary delivery is inconvenient for patients given the discomfort of utilizing a breathing apparatus and the restriction on patient mobility given the need to be close to the breathing apparatus during dosage periods. This is a potentially significant matter, as inconvenience for patients is highly correlated to a lack of patient compliance. Moreover, the inherent toxicity of CO and its odorless, colorless properties make pulmonary delivery use challenging. Storing the amount of CO that would be needed to treat a patient long-term could, in the case of the home, put the patient and other family members in danger, and, in the case of the hospital, would require novel and costly safety precautions such as monitoring and venting before use, and even with such safeguards could put hospital staff in danger.
The utilization of small molecule transition metal-based carriers of CO (referred to herein as Carbon Monoxide Releasing Molecules or “CORMs”) also presents significant challenges for clinical deliver of CO. In linking carbon monoxide to a transition metal, the toxicity of the transition metal is added to the inherent toxicity CO. This transition metal toxicity can limit the acceptable dose and, for certain metals, prevents use in humans completely. Ruthenium and Molybdenum are two of the more widely used transition metals in forming CORMs, and these metals have been categorized as metals of significant safety concern by the European Medicines Agency (EMEA COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP), “GUIDELINE ON THE SPECIFICATION LIMITS FOR RESIDUES OF METAL CATALYSTS OR METAL REAGENTS”, London, 21 Feb. 2008, Doc. Ref. EMEA/CHMP/SWP/4446/2000). This high potential toxicity of CORMs due to the transition metal carriers prevents the use of CORMs in certain indications due to potentially toxicity-limited dosage and also through a more difficult risk:benefit ratio due to the added risk of the transition metal. Particularly unstable patients, including SCD patients, can be particularly at risk. In addition, the toxicity of transition metal carriers presents a significant barrier to recurrent use of CORMs in chronic indications. As SCD is an inherited lifelong condition, long term use of CORMs as a therapy for prevention of SCC is unlikely to be safe as the transition metal carriers will accumulate over time, aggravating the potential toxicity. In summary, the use of transition metal compounds as CO carriers has serious drawbacks as compared to less toxic approaches.
The use of chemically modified hemoglobin tetramers as carriers of CO (cell free CO-Hb) also presents toxicity-related issues. It has been demonstrated that certain significant safety events are associated with the clinical use of hemoglobin tetramer-based oxygen carriers, including myocardial infarction and death, among others (Natanson C, et. al. “Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis”, JAMA. 2008 May 21;299(19):2304-12). The potential toxicity of cell free CO-Hb due to the use of cell free hemoglobin as a CO carrier prevents the use of CO-Hb in certain indications due to potentially toxicity-limited dosage and also through a more difficult risk:benefit ratio due to the added risk of the hemoglobin tetramer. Particularly unstable patients, including SCD patients, can be particularly at risk. In addition, the toxicity of cell free Hb in addition to the potential problematic iron load presents a significant barrier to recurrent use of CO-Hb in chronic indications, including for use in prevention of SCC.
In addition, it has long been known that CO, as most gases, is soluble at low levels at ambient pressure in aqueous solutions. Solutions have previously been prepared in academic laboratories to demonstrate this fact. In addition, aqueous solutions have previously been prepared at ambient pressure and between 4° C. and 21° C., and used ex vivo in non-human studies in order to determine whether delivery of CO by such solutions could improve outcomes in the transplantation of gut, liver, and lung tissues (Nakao A et. al. “Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury”, Am J Transplant. 2006; 6(10):2243-2255; Ikeda, A et. al. “Liver graft exposure to carbon monoxide during cold storage protects sinusoidal endothelial cells and emeliorates reperfusion injury in rats”, Liver Transpl. 2009 November ; 15(11): 1458-1468; Nakao A et. al. “Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts”, Kidney International. 2008; 74:989-991). One study also looked at using such a solution prepared at room temperature and pressure and injected intraperitonealy (referred to herein as “IP”) to investigate whether such a solution could ameliorate postoperative ileus in mice (Atsunori N, et. al., “A Single Intraperitoneal Dose of Carbon Monoxide-Saturated Ringer's Lactate Solution Ameliorates Postoperative Ileus in Mice”, JPET 319:1265-1275, 2006). However, the use of this solution was severely limited. First, in preparing the solution at room temperature and pressure, the amount of dissolved CO was very low. This preparation methodology was necessary in this case because injecting a cold solution could be harmful if directly injected into the peritoneum and, moreover, as the liquid warmed, the CO would bubble out of the solution into the peritoneum which likely would cause potentially severe complications. In addition, while IP delivery is used in non-human research, it is rarely used in treating human disease for both safety and convenience reasons. First, the potential for infection in IP injection is significant, which creates an additional risk to this delivery route. In addition, the inconvenience for patients due to IP delivery can correspond to a lack of patient or physician compliance. Also, in order to allow home IP infusion, a permanent access into the peritoneal space would have to be placed in the patient, similar to that used in IP dialysis. This would add significant inconvenience and also potential morbidities, such as risk of infection, as compared to a non-IP delivery route. Moreover, the IP delivery route relies upon provision of a small amount of CO locally, using direct delivery to the gastrointestinal tract, which is inherently limiting with regard to the treatment of disease.
In summary, to date, there has been no widely suitable, convenient, and safe method for delivery of CO in amounts that would be therapeutic to treat diseases and disorders while avoiding toxicity and providing the necessary level of convenience to those in need.